Neoadjuvant chemotherapy and radiotherapy followed by resection/ ablation in stage IV rectal cancer patients with potentially resectable metastases

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The optimal treatment of stage IV rectal cancer remains controversial. The purpose of this study was to assess the treatment outcomes and toxicity of neoadjuvant chemotherapy and radiotherapy followed by local treatment of all tumor sites and subsequent adjuvant chemotherapy in stage IV rectal cancer patients with potentially resectable metastases.

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Nội dung Text: Neoadjuvant chemotherapy and radiotherapy followed by resection/ ablation in stage IV rectal cancer patients with potentially resectable metastases

Li et al. BMC Cancer (2021) 21:1333 https://doi.org/10.1186/s12885-021-09089-5 RESEARCH Open Access Neoadjuvant chemotherapy and radiotherapy followed by resection/ ablation in stage IV rectal cancer patients with potentially resectable metastases Rongzhen Li1,2†, Qiaoxuan Wang1,2†, Bin Zhang3†, Yan Yuan1,2, Weihao Xie1,2, Xiaoxue Huang1,2, Chengjing Zhou1,2, Shu Zhang1,2, Shaoqing Niu4, Hui Chang1,2, Dongni Chen2,5, Huikai Miao2,5, Zhi Fan Zeng1,2, Weiwei Xiao1,2*† and Yuanhong Gao1,2*† Abstract Background: The optimal treatment of stage IV rectal cancer remains controversial. The purpose of this study was to assess the treatment outcomes and toxicity of neoadjuvant chemotherapy and radiotherapy followed by local treatment of all tumor sites and subsequent adjuvant chemotherapy in stage IV rectal cancer patients with potentially resectable metastases. Methods: Adult patients diagnosed with locally advanced rectal adenocarcinoma with potentially resectable metastases, who received neoadjuvant chemotherapy and radiotherapy from July 2013 and September 2019 at Sun Yat-sen University cancer center, were included. Completion of the whole treatment schedule, pathological response, treatment-related toxicity and survival were evaluated. Results: A total of 228 patients were analyzed with a median follow-up of 33 (range 3.3 to 93.4) months. Eventually, 112 (49.1%) patients finished the whole treatment schedule, of which complete response of all tumor sites and patho- logical downstaging of the rectal tumor were observed in three (2.7%) and 90 (80.4%) patients. The three-year overall survival (OS) and progression-free survival (PFS) of all patients were 56.6% (50.2 to 63.9%) and 38.6% (95% CI 32.5 to 45.8%), respectively. For patients who finished the treatment schedule, 3-year OS (74.4% vs 39.2%, P
Li et al. BMC Cancer (2021) 21:1333 Page 2 of 10 resection rates of merely 5–15% [4–6]. For patients Methods with unresectable metastases, prognosis is poor. Patient population In recent years, with the development of effective We retrospectively reviewed the data of consecutive chemotherapeutic agents, the survival rate of stage patients diagnosed with stage IV rectal cancer who IV rectal cancer significantly improved. In portion of received treatment at Sun Yat-sen University Cancer these patients, effective conversion systemic chemo- Center between July 2013 and September 2019. Their therapy could turn initially unresectable metastases treatment plan was a multimodality schedule, includ- into resectable [7]. Meanwhile, local treatment modal- ing neoadjuvant chemotherapy, pelvic radiotherapy, fol- ities were also developed. Improved surgical tech- lowed by local treatment for both the primary tumor and niques, and the widely used of radiofrequency ablation metastases and subsequent adjuvant chemotherapy. The (RFA) and stereotactic body radiotherapy (SBRT) offer eligibility criteria were: (1) at least 18 years old; (2) patho- a curative chance and do bring survival benefits in logically confirmed rectal adenocarcinoma; (3) primary patients with stage IV rectal cancer [8, 9]. Aggressive lesions were T1–2 with positive regional lymph nodes or multimodality therapy for patients with stage IV rectal T3–4 with both positive and negative lymph nodes; (4) cancer were to achieve the goal of no evidence of dis- synchronous potentially resectable metastases (includ- ease (NED) [10, 11]. However, for the locally advanced ing liver, lung and/or distant lymph nodes) located in no primary tumor and synchronous metastases, resection more than two organs; and (5) a Karnofsky Performance of all tumor sites is still challenging. Therefore, con- Status of at least 70. Patients were excluded if they: (1) verting potentially resectable tumors into a resectable underwent primary tumor resection or metastasectomy or ablationable disease is essential for these patients. before neoadjuvant chemotherapy and radiotherapy; According to the National Comprehensive Cancer (2) had a prior history of other malignancies within five Network (NCCN) guidelines, neoadjuvant chemo- years; (3) severe diseases including heat, brain, lung, therapy and radiotherapy followed by resection is the liver or kidney dysfunction; or (4) metastasis to the standard of care for stage II-III rectal cancer patients peritoneum. [12]. For patients with stage IV rectal cancer, pelvic In clinical practice, an assessment of metastases resect- radiotherapy is often used only as palliative care to ability was conducted by a multidisciplinary team (MDT) relieve local symptoms [13, 14]. Systemic chemother- consisting of radiologists, surgeons, and radiation oncol- apy remains the cornerstone for stage IV rectal cancer ogists. The criteria for potentially resectable liver metas- [15]. For the majority of patients with primary lesions tases in the study were defined as: satisfactory margins at the T3 or T4 stage, researchers are interested in after resection or the residual liver volume preserved is whether adding neoadjuvant chemotherapy and radi- >30% after conversion therapy. Criteria for potentially otherapy could improve the resection rate, improve resectable pulmonary metastases were defined as: adja- local control, and eventually lead to better survival cent to vital structures, such as the great vessels, heart, [16]. In the Dutch phase II clinical trial [17] patients esophagus or centrum, which can be treated with conver- with stage IV rectal cancer received short-course radi- sion therapy to obtain R0 resection. In addition, patients otherapy (SCRT) followed by systemic chemotherapy with distant lymph node metastases vary greatly, and and subsequent radical treatment. The results of the there is no uniformity in the criteria for resectability. It is study showed that 72% of patients achieved R0 resec- related to the experience and surgical skills of the super- tion of both the primary tumor and metastases, and vising surgeons. the 2-year overall survival (OS) was 80%. A respective This research was approved by the Research Eth- study [18] with a similar design showed that 79.4% of ics Committees of Sun Yat-sen University cancer center patients achieved local symptom control and 78% had (B2021–089-01). a chance at liver resection and/or RFA with a median OS of 51.5 months. These indicated that neoadjuvant Pretreatment assessment radiotherapy might bring about some survival benefits Pretreatment assessment consisted of a complete physi- in addition to chemotherapy for stage IV rectal cancer cal examination, carcinoembryonic antigen (CEA) and patients. carbohydrate antigen 19–9 (CA-199) level tests, colo- In this study, we assessed the treatment outcomes noscopy with pathological examination, enhanced and toxicity of this multimodal treatment schedule, magnetic resonance imaging (MRI) or enhanced com- which consisted of neoadjuvant chemotherapy and puterized tomography (CT) of the pelvis (CT was per- radiotherapy, local treatment and adjuvant chemother- formed only in patients with a contraindication to MRI), apy in patients with potentially resectable stage IV rec- and enhanced CT of the chest and abdomen. MRI of the tal cancer. liver was optional when liver metastasis was suspected
Li et al. BMC Cancer (2021) 21:1333 Page 3 of 10 and was performed at the discretion of the attending Outcomes and follow‑up physician. Risk factors considered were patient age (≥60 The primary outcome was OS. Secondary outcomes or 5 whole treatment schedule, pathological response, treat- or ≤ 5 ng/ml), CA199 (> 35 or ≤ 35 U/ml), metastatic ment toxicity, and surgical complications The tumor organs (multiple or single) and number of liver metas- response assessment was conducted using the Response tases (> 5 vs ≤ 5). The 8th edition of the American Joint Evaluation Criteria in Solid Tumors (RECIST) version Committee on Cancer (AJCC) was used to stage patients. 1.0. Treatment toxicity was recorded using the Com- mon Terminology Criteria for Adverse Events (CTCAE) version 4.0. Postoperative complications were evaluated Neoadjuvant treatment and reassessment in accordance with the Clavien-Dindo classification. The treatment schedule for all patients was determined All patients were followed up every three months via an MDT. Chemotherapy started immediately after during the first two years, semiannually over the next diagnosis, with a regimen of CAPOX (capecitabine three years, then annually for the following years. The and oxaliplatin); FOLFOX (fluorouracil, folinic acid last date of follow up was in March 2021. OS was evalu- and oxaliplatin); or capecitabine monotherapy accord- ated from the date of the first treatment to death from ing to the performance status of each patient and at the any cause or censored at the last follow-up. PFS was direction of the treating physicians. Neoadjuvant radio- calculated from the date of the first treatment until the therapy included long-course radiotherapy (LCRT) or diagnosis of the first documented local or distant pro- SCRT given to the rectal tumor, mesorectum and meta- gression, or death related to rectal cancer, whichever static lymph nodes. Intensity-modulated technology was came first. Completion of the treatment schedule was applied in this study. LCRT consisted of 50Gy delivered defined as finishing neoadjuvant chemotherapy and in 25 fractions and was started concurrently with the 2nd radiotherapy, subsequent local treatment for all tumor cycle of chemotherapy. Five weeks after LCRT, patients sites and at least 2 cycles of adjuvant chemotherapy. were reassessed by colonoscopy, an enhanced CT scan of chest and abdomen, an enhanced MRI of the pelvis and a CEA level test. SCRT consisted 25Gy delivered Statistical analysis in 5 fractions and was given after finishing 4–6 cycles The statistical analysis was carried out with SPSS ver- of chemotherapy and no concurrent chemotherapy was sion 26.0 (IBM, Armonk, NY, USA) and R version given. Reassessment was performed before the decision 4.0.4 (http://w ww.Rproject.org). Statistical data were to receive SCRT (Supplementary Fig. 1). reported as medians with ranges, and the categori- cal data were reported in proportions. Survival curves were displayed by Kaplan-Meier analysis, and the sur- Surgery and postoperative adjuvant chemotherapy vival rates compared by using the log-rank test. A Cox After reassessment, the ability to resect the primary proportional hazards regression was used to examine tumor and metastases was discussed by the MDT. the independent prognostic factors by calculating the According to the examination results, the MDT deter- hazard ratios (HR) and 95% confidence intervals (CI) in mined the next procedure: palliative treatment, staggered univariate and multivariate analyses. A p value of
Li et al. BMC Cancer (2021) 21:1333 Page 4 of 10 Fig. 1 Flowchart for all patients in the study. Abbreviations: LCRT, long-course radiotherapy; SCRT, short-course radiotherapy paraaortic lymph nodes and the left supraclavicular Overall and progression‑free survival lymph nodes (28 patients, 12.3%). Seventy patients (30.7%) developed progressive diseases during treatment and 79 patients (34.6%) had disease progression after treatment to the last follow up or death Completion of treatment schedule for the whole cohort. Liver and lung were the most com- All patients received neoadjuvant chemotherapy and mon sites of the progression. Only 7 patients (3.1%) had pelvic intensity-modulated radiation therapy (IMRT). local progression, of them, three occurred during treat- LCRT and SCRT were given to 204 patients (89.5%) ment and four occurred after treatment (Table 3). The and 24 patients (10.5%), respectively. After neoad- median OS for all patients was 41.7 (range 3.3 to 93.4) juvant treatment, 100 patients (41.0%) received a months and the 1–2-and 3-year OS rates were 91.2% bowel-first approach, 20 patients (8.2%) received a (95% CI 87.6 to 95%), 74.8% (69.4 to 80.7%) and 56.6% metastases first approach and simultaneous resection (50.2 to 63.9%), respectively. Median PFS for all patients was performed in 37 patients (15.2%). Three patients was 20.5 (range 0.7 to 93.4) months and the 1–2-and (1.2%) had a clinical complete response (cCR) to both 3-year PFS rates were 67.4% (95% CI, 61.5 to 73.8%), the primary rectal tumor and distant metastases. The 43.7% (95% CI, 37.6 to 50.7%) and 38.6% (95% CI, 32.5 to number of patients who finished the whole treatment 45.8%), respectively. schedule was 112 (49.1%) (Fig. 1). In the subgroup analysis, we found that the median OS Of the 116 patients who were not able to complete of the 112 patients who completed the whole treatment the treatment schedule, 50 patients (21.9%) received schedule was 55.5 months, compared with 30.7 months palliative treatment, 33 patients (14.5%) received for patients who did not complete treatment (P
Li et al. BMC Cancer (2021) 21:1333 Page 5 of 10 Table 1 Patient demographics and disease characteristics Table 2 Treatment details (n = 228) (n = 228) Characteristics No. of patients (%) Characteristics No. of patients (%) b Radiotherapy Age at start of treatment a (years) 56 (25–81) 25 × 2Gy 204 (89.5) Sex ratio (M: F) 160: 68 5 × 5Gy 24 (10.5) KPS First-line chemotherapy 70–80 26 (11.4) CAPOX 180 (78.9) 90–100 202 (88.6) CAPOX-B 9 (3.9) Clinical tumor category FOLFOX 10 (4.4) T2 N1–2 2 (0.9) FOLFOX-B 7 (3.1) T3 N0 2 (0.9) CAP 15 (6.6) T3 N1–2 95 (41.7) CAP-B 2 (0.9) T4 N1–2 129 (56.6) Other 5 (2.2) Metastatic site Time of chemotherapy (months) Liver 116 (50.9) ≤3 23 (10.1) Lung 64 (28.1) 3–6 131 (57.5) Liver and lung 20 (8.8) > 6 74 (32.5) Distant lymph nodes 28 (12.3) Rectal resection n = 142 No. of liver metastases n = 116 Low anterior resection 116 (81.7) 1–3 78 (67.2) Abdominoperineal resection 20 (14.1) 4–5 9 (7.8) Hartmann procedure 6 (4.2) ≥6 29 (25) Diverting stoma n = 73 Location of liver metastases n = 136 Simultaneous surgery 50 (68.5) Unilobar 52 (38.2) During chemotherapy 15 (20.5) Multilobar 84 (61.8) Before treatment 8 (11.0) Diameter of largest liver metastasis a (cm) 2.0 (0.6–12) pTRG (Mandard) a n = 129 Length of rectal cancer a (cm) 5.5 (1.5–16) Complete regression (TRG 1) 25 (19.4) Location of primary rectal cancer Good regression (TRG 2) 49 (38.0) Low (0-5 cm) 61 (26.8) Moderate regression (TRG 3) 41 (31.8) Middle (5-10 cm) 134 (58.8) Slight regression (TRG 4) 14 (10.9) High (10-15 cm) 33 (14.5) Liver treatment n = 85 Differentiation Liver resection 30 (35.3) Well 9 (3.9) RFA 33 (38.8) Moderate 177 (77.6) Resection + RFA 18 (21.2) Poor 31 (13.6) Radiotherapy 4 (4.7) Unknown 11 (4.8) Treatment of extrahepatic metastases CEA at diagnosis a (ng/ml) 14.6 (0.7–2677) Lung CA199 at diagnosis a (U/ml) 31.4 (0.6–20,000) RFA 22 (9.6) a Values are median (range). bWith percentages in parentheses unless indicated Metastasectomy 7 (3.1) otherwise Radiotherapy 2 (0.9) Abbreviations: KPS Karnofsky Performance Status, CEA carcinoembryonic Lymph node resection 6 (2.6) antigen, CA199 carbohydrate antigen 19–9 Rectal radiotherapy expanded for lymph node 28 (12.3) a pathological tumor regression grade of 5-tier Mandard adjuvant Abbreviations: B bevacizumab, RFA radiofrequency ablation, CAP capecitabine, 112 patients was 24.7 (range 0.8 to 93.4) months, and the OX oxaliplatin; FOLFOX, 5-fluorouracil, folinic acid and oxaliplatin 1–2-and 3-year PFS rates were 76.8% (95% CI, 69.4 to 85.0%), 51.4% (95% CI, 42.8 to 61.6%) and 45.5% (95% CI, 36.8 to 56.2%), respectively. For patients who finished the treatment schedule, 3-year OS (74.4% vs 39.2%, P
Li et al. BMC Cancer (2021) 21:1333 Page 6 of 10 Table 3 Location of progression of disease during and after were not statistically significant on multivariable analy- treatment sis for OS (Supplementary Table 2). Location During After treatment treatment Evaluation of radiological and pathological responses The cCR of all the tumor sites were observed in three Liver 24 23 out of 228 patients (1.2%) and they were given a watch Lung 18 27 and wait strategy after a total of six months of chemo- Rectum 3 4 therapy. One of these patients had liver recurrence five Liver and lung 11 6 months after finishing treatment and was given pallia- Liver, lung and lymph nodes 3 5 tive treatment. Other patients did not experience recur- Peritoneum 5 4 rence during a median follow-up of 32 months. Clinical Bone 4 3 partial response occurred in 130 patients (57.0%) after Other 2 7 neoadjuvant chemotherapy and radiotherapy. Primary rectal surgery was conducted in 142 patients (62.3%) and R0 resection was achieved in 137 patients (96.5%). Of these patients, 25 (17.6%) presented a pathological complete response (pCR) and 74 (52.1%) showed a good Fig. 2 Kaplan–Meier analysis of overall survival (A) and progression-free survival (B) for the whole cohort, patients who completed the treatment schedule, and those who did not Table 4 Univariable and multivariable analysis for progression-free survival Univariable analysis Multivariable analysis Factor Hazard ratio P Hazard ratio P Age (> 60 vs ≤ 60 a) 1.15 (0.72, 1.84) 0.553 Sex (M vs F a) 1.04 (0.65, 1.67) 0.865 cT category (IV vs II-III a) 1.62 (0.62, 2.58) 0.045 0.98 (0.62, 1.54) 0.916 cN category (II vs 0-I a) 1.07 (0.94, 1.73) 0.791 CEA (> 5 or ≤ 5 a,b) 1.17 (0.71, 1.92) 0.531 CA199 (> 35 or ≤ 35 a,c) 1.02 (0.65, 1.61) 0.929 Metastatic organs (Multiple vs single a) 1.06 (0.42, 2.64) 0.089 No. of liver metastases (> 5 vs ≤ 5 a) 1.25 (0.96, 2.84) 0.008 1.18 (0.30, 2.89) 0.028 a b c The control group of multivariate Cox analysis. The normal values for CEA range 0–5 ng/ml. The normal values for CA199 range 0–35 U/ml Abbreviations: M male, F female, cT category clinical T category, cN category clinical N category, CEA carcinoembryonic antigen, CA199 carbohydrate antigen 19–9
Li et al. BMC Cancer (2021) 21:1333 Page 7 of 10 pathological tumor regression grade (TRG1 and TRG2). neoadjuvant chemotherapy and radiotherapy followed They were given postoperative chemotherapy. Patho- by resection/ablation and subsequent adjuvant chemo- logical downstaging of the rectal tumor was observed in therapy achieved long-term survival with a relatively low 90 patients (80.4%). Surgical resection of liver and lung recurrence rate and tolerable toxicities in rectal cancer metastases were conducted in 48 (21.1%) and seven patients with potentially resectable synchronous metas- (3.1%) patients, with a pCR of the liver and lung were tases, demonstrating the feasibility of this treatment respectively reported in six (12.5%) and one (14.3%) schedule. patient among them. The imaging characteristics of stage Neoadjuvant chemotherapy and radiotherapy provide IV rectal cancer patients with liver or lung metastases survival benefit over chemotherapy alone in down-stag- after neoadjuvant chemotherapy and radiotherapy are ing of the primary lesion and in converting potentially presented in Supplementary Fig. 2. resectable metastases into a resectable or ablatable dis- ease. In a national database analysis [21] conducted with Toxicities and complications 4051 patients with metastatic rectal adenocarcinoma, Grade 3–4 toxicities were observed in 50 patients (21.9%) the median OS was 46.3 months versus 35.3 months during neoadjuvant treatment, with hematological toxic- in favor of additional radiotherapy. In a phase II clini- ity reported mostly frequently in 27 patients (11.8%) and cal trial [22], 32 patients with synchronous unresectable gastrointestinal toxicity reported in 13 patients (5.7%). metastases of rectal cancer underwent radical surgery of For hematological toxicity, 14 and 13 patients had throm- the primary tumor and 85.7% of them showed a patho- bocytopenia and neutropenia, respectively. Patients logical down-staging of the primary tumor after neoadju- were given symptomatic management and all completed vant chemotherapy and radiotherapy. In addition, 35.7% neoadjuvant treatment. Surgical complications were of these patients had a pathological complete response. observed in 22 patients (9.6%) (Table 5). The most com- However, in a small sample sized piece of research [23], mon complications were intestinal obstruction observed Milito P et al. reported a 3-year local regional recur- in 14 patients (6.1%), with only six of them requiring sur- rence-free survival (LRRFS) rate of 80.3% for neoadjuvant gical intervention. Five patients (2.2%) had anastomotic chemotherapy and radiotherapy vs. 90.4% for upfront leakage and four of them were treated with enterostomy. surgery patients (P = 0.35). This is inconsistent with our No patients died as a result of surgical side effects. results. Nevertheless, this inconsistency may be due to differences in patient selection. In Milito P’s study, only Discussion patients with a resectable primary tumor were included. Currently, the optimal treatment of stage IV rectal can- In contrast, in this present study, most patients had a cer remains unclear [19]. In the context of a locally locally advanced primary tumor and potentially resect- advanced primary tumor with synchronous metastasis, able metastases at baseline and the opportunity of radical an effective treatment schedule should combine locore- resection for all tumor sites depended on the response gional control with an adequate dose of systemic chem- to neoadjuvant chemotherapy and radiotherapy. Even- otherapy for all tumor sites [20]. In this present study, tually, 134 patients (58.9%) received local treatment for metastases and 142 patients (62.3%) received radical rectal surgery, of which more than half of them (57.4%) were pathologically confirmed as having good regression Table 5 Neoadjuvant treatment toxicity and local treatment of the rectal tumor. In our study, pelvic radiation signifi- complications cantly reduced the risk of rectal bleeding and obstruction Events Grade 3 Grade 4 Total during treatment compared with previous studies [24, no. of patients 25] and contributed to the relatively low recurrence rate after the whole treatment schedule. Chemoradiotherapy-related toxicity Local treatment of metastases and resection of primary Hematological 23 4 27 tumors could diminish tumor burden and reach a clini- Gastrointestinal 10 3 13 cally NED for patients. As is well known, surgical resec- Neurological 5 0 5 tion, RFA and SBRT are common local treatments for Dermatological 3 2 5 metastases, and earlier studies [26, 27] have shown that Surgical complications there are no differences in survival time among them. Intestinal obstruction 8 6 14 Currently, there is a trend to adopt the watch and wait Anastomotic leakage 5 0 5 strategy for complete responders of locally advanced Anastomotic stenosis 2 0 2 rectal cancer after neoadjuvant chemoradiotherapy. Our Abscess 1 0 1 previous study [28] showed that compared to standard
Li et al. BMC Cancer (2021) 21:1333 Page 8 of 10 TME, the watch and wait strategy got similar survival options. In this study, the treatment of all patients with outcomes and a superior sphincter preservation for potentially resectable metastases was discussed by the stage II/III rectal cancer patients. However, all the avail- MDT group, and this, to some extent made the assess- able data discussing this topic currently applied only to ment more objective. Second, as a retrospective inves- patients without distant metastasis. As the adding of tigation conducted in a single center, this study had radiotherapy and more cycles of chemotherapy, or even inherent selection bias. Large prospective randomized total neoadjuvant chemotherapy in stage IV diseases, controlled clinical trials are needed to verify these results there are also chances of complete response in primary to provide the optimal treatment schedule for these tumor. In this study, complete response was observed in patients. 19.4% of patients who underwent surgical resection of the primary tumor and the 3-year OS was up to 91.4%. For these patients, the watch and wait strategy might be Conclusions an option, especially for distal rectal cancers. Clinical tri- Neoadjuvant chemotherapy and radiotherapy followed als discussing the watch-and-wait strategy for this sub- by surgery/ablation and adjuvant chemotherapy offered group of patients are warranted to verify this hyposis. chances of long-term survival with tolerable toxicities in Recurrence of distant metastasis remains the main potentially resectable stage IV rectal cancer patients, and treatment problem for these patients. The high rate of could be considered as an option in clinical practice. early recurrence is consistent with other research [29, 30], with nearly half of patients developing disease recur- Abbreviations rence within two years of starting treatment. In view of OS: Overall survival; PFS: Progression-free survival; RFA: Radiofrequency abla- the high recurrence and poor prognosis of stage IV rectal tion; SBRT: Stereotactic body radiotherapy; NCCN: National Comprehensive cancer, most patients were offered a total of six months Cancer Network; SCRT: Short-course radiotherapy; CEA: Carcinoembryonic antigen; CA-199: Carbohydrate antigen 19–9; AJCC: American Joint Commit- chemotherapy to eliminate small and potentially occult tee on Cancer; MDT: Multidisciplinary team; CAPOX: Capecitabine and oxali- metastases early in this present study. However, there platin; FOLFOX: Fluorouracil, folinic acid and oxaliplatin; LCRT: Long-course were still 34.6% of patients who had disease progression radiotherapy; TME: Total mesorectal excision; RECIST: Response Evaluation Criteria in Solid Tumors; CTCAE: Common Terminology Criteria for Adverse after treatment. Immunotherapy, targeted therapies and Events; HR: Hazard ratios; CI: Confidence intervals; cCR: Clinical complete triplet chemotherapy which might facilitate the removal response; pCR: Pathological complete response; TRG: Tumor regression grade; of potential micrometastasis and the strategy of total NED: No evidence of disease; LRRFS: Local regional recurrence-free survival. neoadjuvant therapy could be considered, to improve the treatment efficacy [31, 32]. Supplementary Information This treatment schedule was relatively safe and toler- The online version contains supplementary material available at https://doi. org/10.1186/s12885-021-09089-5. able, even though long-term radiotherapy, multi-course chemotherapy and various local treatments were given Additional file 1: Supplementary Figure 1. The most common treat- to the majority of patients. Bone marrow suppression ment modal of neoadjuvant chemotherapy and radiotherapy. and gastrointestinal reactions including nausea, diar- Additional file 2: Supplementary Figure 2. Representative images rhea and ileus were the most common side effects dur- before and after neoadjuvant therapy in stage IV rectal cancer patients ing radiotherapy and chemotherapy, which is consistent with synchronous metastases (red arrows). A. MRI imaging showing the with the results from previous research [33]. In this disappearance of synchronous liver metastases after neoadjuvant therapy. B. CT imaging showing the disappearance of synchronous lung metasta- study, all patients finished the full dose of radiotherapy ses after neoadjuvant therapy. without intolerable toxic effects. Similar with other stud- Additional file 3: Supplementary Table 1. Patient demographics and ies [34, 35], anastomotic leakage was the most frequently disease characteristics (n = 228). reported surgical complication apart from intestinal Additional file 4: Supplementary Table 2. Univariable and multivariable obstruction, but most were manageable with a diverting analysis for overall survival. colostomy. No lethal adverse events occurred throughout this study’s entire treatment schedule. Acknowledgments To the best of our knowledge, this study comprised of We thank all the clinicians and patients who participated in this study. one of the largest stage IV rectal cancer patient cohorts Authors’ contributions who underwent neoadjuvant chemotherapy and radio- R.Z.L, Y.H.G. and W.W.X. had the original idea for the study. Y.H.G. and R.Z.L. had therapy followed by radical surgery and local treatment, access to all data in the study, and were responsible for the integrity of the data. R.Z.L., B.Z. and Y.Y. participated in analyzing the data and writing of the with clinical values for subsequent research. However, manuscript. Q.X.W. and W.W.X. were involved in the revision of the manuscript. we acknowledge there are some limitations of this study. S.Q.N., W.H.X., C.J.Z. and X.X.H. were involved in the design of the study. S.Z., First, the assessment of potentially resectable metasta- D.N.C., H.K.M., Z.F.Z and H.C. collected the data. All authors reviewed the final version of the manuscript and approved the submitted version. ses remains unclear and was influenced by subjective
Li et al. BMC Cancer (2021) 21:1333 Page 9 of 10 Funding 11. Angelsen JH, Horn A, Sorbye H, Eide GE, Løes IM, Viste A. Population- This work was supported by the National Natural Science Foundation of China based study on resection rates and survival in patients with colorectal (82073329), and the Natural Science Foundation of Guangdong Province liver metastasis in Norway. Br J Surg. 2017;104(5):580–9. (2020A1515011286). 12. Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, et al. NCCN Guidelines Insights: Rectal Cancer, Version 6.2020. J Natl Availability of data and materials Compr Cancer Netw. 2020;18(7):806–15. All data are available via the corresponding author. 13. Wang G, Wang W, Jin H, Dong H, Chen W, Li X, et al. The effect of primary tumor radiotherapy in patients with Unresectable stage IV rectal or Rectosigmoid Cancer: a propensity score matching analysis for survival. Declarations Radiation oncology (London, England). 2020;15(1):126. 14. Gelsomino F, Spallanzani A, Garajova I. The treatment of rectal cancer Ethics approval and consent to participate with synchronous liver metastases: a matter of strategy. Crit Rev Oncol This observational study was performed in accordance with the Declaration Hematol. 2019;139:91–5. of Helsinki and approved by the Medical Ethics Committee of Sun Yat-sen 15. Li Y, Wang J, Ma X, Tan L, Yan Y, Xue C, et al. A review of neoadjuvant University Cancer Center (B2021–089-01). All patients provided informed Chemoradiotherapy for locally advanced rectal Cancer. Int J Biol Sci. consent before treatment. 2016;12(8):1022–31. 16. Socha J, Bujko K. Are we already in the era of total neoadjuvant treatment Consent for publication for rectal cancer? The Lancet Oncology. 2021;22(5):575–7. Not applicable. 17. van Dijk TH, Tamas K, Beukema JC, Beets GL, Gelderblom AJ, de Jong KP, et al. 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